Cocaine, a widely abused stimulant, is thought to produce its reinforcing effects primarily through the dopamine system. Yet no effective treatment agents for cocaine abuse have been developed to date. Moreover, few human experimental studies have examined the behavioral interactions between cocaine and possible treatment agents. Therefore, the major aim of this project is to establish a model for assessing cocaine abuse liability in humans; that is, a drug discrimination procedure. In the drug discrimination procedure, subjects are trained to distinguish between a dose of cocaine (80 mg/70 kg, p.o.) and placebo and then tested with different doses of cocaine to obtain a dose-effect curve. Subsequently, the effects of possible treatment agents are examined alone and in combination with cocaine to determine whether these agents produce cocaine-like effects or alter cocaine's effects. In experiment l, the pharmacological specificity of the cocaine discriminative stimulus will be tested by examining the effects of other CNS stimulants such as mazindol (0-3 mg/70 kg) and d-amphetamine (0-20 mg/70 kg) and a sedative compound such as triazolam (0.0-0.56 mg/70 kg) in cocaine-discriminating subjects. Then in experiments 2-5, cocaine's effects alone and in combination with one of the following compounds will be examined: the D2 antagonist haloperidol (0-8 mg/70 kg), the Dl, D2 antagonist flupenthixol (0-2 mg/70 kg), and a Dl antagonist soon to be available from Schering (i.e., SCH23390). In addition to discrimination measures, the following will be assessed: l) self-reported effects, as a traditional measure of abuse liability; 2) acoustic startle, as an objective measure of CNS reactivity and possible model for assessing cocaine sensitization; and 3) physiological measures. These measures will provide a wide behavioral profile to compare the degree to which agents acting on differing dopaminergic mechanisms alter cocaine's effects. The development of this paradigm will also provide a standard, objective methodology to assess the behavioral interactions between cocaine and test compounds which show promise as treatment agents based on the research conducted in Projects 5 and 6.